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Molecular and Cellular Biochemistry

, Volume 305, Issue 1–2, pp 63–69 | Cite as

The role of gender differences in beta-adrenergic receptor responsiveness of diabetic rat heart

  • Ayca Bilginoglu
  • Figen Amber Cicek
  • Mehmet Ugur
  • Hakan Gurdal
  • Belma Turan
Article

Abstract

Since the mechanisms responsible for gender differences in cardiac contractile function have not been fully elucidated, we focused to determine the effect of gender difference on β-adrenergic receptors (β-ARs) signal transduction in ventricular cardiomyocytes from insulin-dependent diabetic (streptozotocin-induced) rats. Dose-response curves of left ventricular developed pressure (LVDP) to isoproterenol (ISO) in females showed that there was only a ∼30% decrease in the maximum response without a significant shift in EC50 in diabetic females. On the other hand, diabetes induced a clear rightward shift in the potency (5–10 folds) without a significant change in the maximum response in the males. In order to further determine of the underlying mechanism for this difference, we measured cAMP production and obtained dose-response curves with ISO stimulation in isolated cardiomyocytes. In diabetic females, there was no obvious change in the cAMP dose-response curve. On the other hand, there was a significant decrease in the maximum response without any apparent change in the potency of diabetic males. Our findings indicate that male and female rats are affected differently by diabetes in terms of LVDP responses to β-ARs stimulation. Also, the difference between their β-ARs induced cAMP responses may underlie this disparity.

Keywords

Diabetes Gender differences Beta-adrenergic signal transduction cAMP G-proteins Cardiomyopathy 

Notes

Acknowledgements

This work has been supported by grants of Ankara University project 2006-080-9233 and projects of TUBITAK-SBAG-PIA-10 (105S149) and TUBITAK-SBAG-3056 (104S591).

References

  1. 1.
    Schaible TF, Scheuer J (1984) Comparison of heart function in male and female rats. Basic Res Cardiol 79:404–412CrossRefGoogle Scholar
  2. 2.
    Schwertz DW, Beck JM, Kowalski JM, Ross JD (2004) Sex differences in the response of rat heart ventricle to calcium. Biol Res Nurs 5(4):286–298PubMedCrossRefGoogle Scholar
  3. 3.
    Capasso JM, Remily RM, Smith RH, Sonnenblick EH (1983) Sex differences in myocardial contractility in the rat. Bas Res Cardiol 78:156–171CrossRefGoogle Scholar
  4. 4.
    Curl CL, Wendt IR, Kotsanas G (2001) Effects of gender on intracellular [Ca2+] in rat myocytes. Eur J Physiol 441:709–716CrossRefGoogle Scholar
  5. 5.
    Ayaz M, Ozdemir S, Ugur M, Vassort G, Turan B (2004) Effects of selenium on altered mechanical and electrical cardiac activities of diabetic rat. Arch Biochem Biophys 426:83–90PubMedCrossRefGoogle Scholar
  6. 6.
    Ozdemir S, Ugur M, Gurdal H, Turan B (2005) Treatment with AT(1) receptor blocker restores diabetes-induced alterations in intracellular Ca(2+) transients and contractile function of rat myocardium. Arch Biochem Biophys 435:166–174PubMedCrossRefGoogle Scholar
  7. 7.
    Bedinghaus J, Leshan L, Diehr S (2001) Coronary artery disease prevention: what’s different for women? Am Fam Physician 63:1393–1400PubMedGoogle Scholar
  8. 8.
    Johnson BE, Johnson CA (2001) Cardiovascular disease and differences between the sexes. Am Fam Physician 63:1290–1292PubMedGoogle Scholar
  9. 9.
    Stone PH, Thompson B, Anderson HV, Kronenberg MW, Gibson RS, Rogers WJ, Diver DJ, Theroux P, Warnica JW, Nasmith JB, Kells C, Kleiman N, McCabe CH, Schactman M, Knatterud GL, Braunwald E (1996) Influence of race, sex, and age on management of unstable angina and non-Q-wave myocardial infarction: the TIMI III registry. JAMA 275:1104–1112PubMedCrossRefGoogle Scholar
  10. 10.
    Luzier AB, Nawarskas JJ, Anonuevo J, Wilson MF, Kazierad DJ (1998) The effects of gender on adrenergic receptor responsiveness. J Clin Pharmacol 38(7):618–624PubMedGoogle Scholar
  11. 11.
    Rodrigues B, McNeill JH (1987) Comparison of cardiac function in male and female diabetic rats. Gen Pharmacol 18(4):421–423PubMedGoogle Scholar
  12. 12.
    Sellers DJ, Chess-Williams R (2001) The effect of streptozotocin-induced diabetes on cardiac beta-adrenoceptor subtypes in the rat. J Autonomic Pharmacol 21(1):15–21CrossRefGoogle Scholar
  13. 13.
    Gando S, Hattori Y, Akaishi Y, Nishihira J, Kanno M (1997) Impaired contractile response to beta adrenoceptor stimulation in diabetic rat hearts: alterations in beta adrenoceptors-G protein-adenylate cyclase system and phospholamban phosphorylation. J Pharmacol Exp Ther 282:475–484PubMedGoogle Scholar
  14. 14.
    Austin C, Williams RC (1993) The in-vitro effects of insulin and the effects of acute fasting on cardiac β-Adrenoceptor responses in the short-term streptozotocin-diabetic rat. J Pharm Pharmacol 46:326–331Google Scholar
  15. 15.
    Atkins FL, Dowell RT, Love S (1985) β-Adrenergic receptors, adenylate cyclase activity and cardiac dysfunction in the diabetic rat. J Cardiovasc Pharmacol 7:66–70PubMedCrossRefGoogle Scholar
  16. 16.
    Kaul CL, Grewal RS (1980) Increased urinary excretion of catecholamines and their metabolites in streptozotocin diabetic rats. Pharmacology 21:223–228PubMedCrossRefGoogle Scholar
  17. 17.
    Neubauer B, Christensen NJ (1976) Norepinephrine, epinephrine and dopamine contents of the cardiovascular system in long-term diabetes. Diabetes 25:6–10PubMedCrossRefGoogle Scholar
  18. 18.
    Sato N, Hashimoto H, Takiguchi Y, Nakashima M (1989) Altered responsiveness to sympathetic nerve stimulation and agonists of isolated left atria of diabetic rats: no evidence for involvement of hypothyroidism. J Pharmacol Exp Ther 248:367–371PubMedGoogle Scholar
  19. 19.
    Sayar K, Ugur M, Gurdal H, Onaran O, Hotomaroglu O, Turan B (2000) Dietary selenium and vitamin E intakes alter β-Adrenergic response of L-Type Ca-current and β-Adrenoceptor-Adenylate cyclase coupling in rat heart. J Nutr 130:733–740PubMedGoogle Scholar
  20. 20.
    Brodde OE, Michel MC (1999) Adrenergic and muscarinic receptors in the human heart. Pharmacol Rev 51(4):651–690PubMedGoogle Scholar
  21. 21.
    Heyliger C, Pierce G, Singal P, Beamish R, Dhalla NS (1982) Cardiac alpha and beta-adrenergic receptor alterations in diabetic cardiomyopathy. Basic Res Cardiol 77:610–618PubMedCrossRefGoogle Scholar
  22. 22.
    Ramanadham S, Tenner TE (1987) Alterations in the myocardial β-AR system of streptozotocin-diabetic rats. Eur J Pharmacol 136:377–389PubMedCrossRefGoogle Scholar
  23. 23.
    Yu Z, McNeill JH (1991) Altered inotropic responses in diabetic cardiomyopathy and hypertensive-diabetic cardiomyopathy. J Pharmacol Exp Ther 257:257–264Google Scholar
  24. 24.
    Sunderesan PR, Sharma VK, Gingold SL, Banerjee PS (1984) Decreased beta adrenergic receptors in rat heart in streptozotocin-induced diabetes: role of thyroid hormones. Endocrinology 114:1358–1363CrossRefGoogle Scholar
  25. 25.
    Du XJ (2004) Gender modulates cardiac phenotype development in genetically modified mice. Cardiovasc Res 63:510–519PubMedCrossRefGoogle Scholar
  26. 26.
    Dincer UD, Bidasee KR, Guner S, Tay A, Ozcelikay AT, Altan VM (2001) The effect of diabetes on expression of β1-, β2-, and β3-adrenoreceptors in rat hearts. Diabetes 50:455–461PubMedCrossRefGoogle Scholar
  27. 27.
    Matsuda N, Hattori Y, Gando S, Akaishi Y, Kemnotsu O, Kanno M (1999) Diabetes-induced down-regulation of β1-AR mRNA expression in rat heart. Biochem Pharmacol 58:881–885PubMedCrossRefGoogle Scholar
  28. 28.
    Minneman KP, Hedberg A, Molinoff PB (1979) Comparison of beta-adenergic receptor subtypes in mammalian tissues. J Pharmacol Exp Ther 211:502–508PubMedGoogle Scholar
  29. 29.
    Bryan LJ, Cole JJ, O’Donnell SR, Wantstall JC (1981) A study designed to explore the hypothesis that beta-1 ARs are “innervated” receptors and beta-2 ARs are “hormonal” receptors. J Pharmacol Exp Ther 216:395–400PubMedGoogle Scholar
  30. 30.
    Babiker FA, De Windt LJ, van Eickels M, Groke C, Meyer R, Doevendans PA (2002) Estrogenic hormone action in the heart: regulatory network and function. Cardiovasc Res 53:709–719PubMedCrossRefGoogle Scholar
  31. 31.
    Grady D, Herrington D, Bittner V, Blumenthal R, Davidson M, Hlatky M, Hsia J, Hulley S, Herd A, Khan S, Newby LK, Waters D, Vittinghoff E, Wenger N, HERS Research Group (2002) Cardiovascular disease outcomes during 6.8 years of hormone therapy: heart and estrogen/progestin replacement study follow-up (HERS II). JAMA 288(1):49–57. Erratum in: JAMA 2002, 288(9):1064Google Scholar
  32. 32.
    Manson JE, Hsia J, Johnson KC, Rossouw JE, Assaf AR, Lasser NL, Trevisan M, Black HR, Heckbert SR, Detrano R, Strickland OL, Wong ND, Crouse JR, Stein E, Cushman M, Women’s Health Initiative Investigators (2003) Estrogen plus progestin and the risk of coronary heart disease. N Engl J Med 49(6):523–534Google Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  • Ayca Bilginoglu
    • 1
  • Figen Amber Cicek
    • 1
  • Mehmet Ugur
    • 1
  • Hakan Gurdal
    • 2
  • Belma Turan
    • 1
  1. 1.Department of Biophysics, School of MedicineAnkara UniversityAnkaraTurkey
  2. 2.Department of Pharmacology, School of MedicineAnkara UniversityAnkaraTurkey

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